Oral Manifestation of Viral-Induced Erythema Multiforme Major: A Rare Presentation

Abstract

Erythema multiforme is an acute inflammatory mucocutaneous disease manifested as macules, vesicles, bullae, erosion, and papular lesions. In the present case, a 55-year-old female patient reported painful growth in the oral cavity and difficulty in mastication. The patient gave a history of prodromal symptoms before the onset of lesions On intra-oral examination, elevated plaque-like lesions were present bilaterally on lateral borders of the tongue and buccal mucosa near the retromolar region. Extraoral examination revealed concentric erythematous target (or) bull’s eye lesions in palms, forearm, and foot. Based on history, clinical examination, and laboratory investigations, recurrent herpes-associated erythema multiforme was diagnosed. We report a rare clinical presentation of recurrent herpes-associated erythema multiforme manifesting as an extensive plaque-like lesion intra-orally.

Introduction

Erythema multiforme (EM) is an acute blistering, ulcerative mucocutaneous condition of uncertain etiopathogenesis. Drug intake and several infections are the common etiologic factors that can induce erythema multiforme. Prodromal symptoms like fever, lymphadenopathy, headache, malaise, sore throat and polyarthralgia may occur one week prior to the onset of lesions. [1] Specifically, herpes simplex virus (HSV) infection has been reported in up to 70% of EM cases [2].

As the word multiforme implies, the appearance of the cutaneous rash can be quite varied such as macule, papule and vesicles which collapse and gradually enlarge to form large lesions on the skin. The typical target iris lesion comprises central bullae with a dusky oedematous center and an erythematous halo [3]. Isolated mucosal (ocular or oral) EM, known as Fuchs syndrome, may be recurring and predominantly associated with the herpes virus and, at times, with Mycoplasma pneumoniae infection. [4, 5].

Intra-oral presentation is commonly an erythematous macule followed by necrosis, bullae, ulceration and encrustation [6]. However, plaque-like manifestation has not been reported yet in the oral cavity. We present an uncommon case report of recurrent herpes-associated erythema multiforme manifesting as extensive plaque in the oral cavity.

Case Report

A 55-year-old woman presented to outpatient department of a private dental college, with the chief complaint of pain and growth in both buccal mucosa and bilateral borders of the tongue and difficulty in swallowing and mastication for the past ten days duration. The onset was spontaneous. Her past medical history revealed two episodes of prodromal symptoms like fever, malaise, headache, cough and sore throat in the past and she reported similar episodes for a week prior to the onset of present lesions. The family and systemic history of the patient were non-contributory.

The oral lesions were presented as bilateral elevated plaque-like lesions with brownish-black discoloration, which is indicative of necrosis of the lesion in the tongue (Fig. 1A & B) and buccal mucosa near the retromolar region (Fig. 1C). The skin rash was characterized by concentric erythematous target (or) bull’s eye lesions in the palms, forearm and foot (Fig. 1D). The differential diagnoses included herpes-associated erythema multiforme, dermatitis herpetiformis, eczema herpeticum, bullous pemphigus or pemphigoid and linear IgA dermatosis.

Fig. 1.

A Picture shows dorsum of the tongue with erythematous eruptions. A1 Post therapy picture shows entirely healed dorsum of the tongue. B The left lateral border of the tongue shows an extensive plaque-like lesion with necrosis. B1 Post therapy picture shows entirely healed lesion on the left side lateral border of the tongue. C The right buccal mucosa shows an extensive plaque like lesion with necrosis. C1 Post therapy picture shows entirely healed lesion on the right buccal mucosa. D Typical target-iris lesions on the left palm. D1 Post therapy picture shows entirely healed lesion on the left palm.

The patient’s laboratory investigations revealed a normal complete blood count and erythrocyte sedimentation rate (ESR) but with an elevated IgM and IgG antibody titer against HSV. Based on the presentation, history, time course, clinical examination and laboratory investigations, she was diagnosed with recurrent herpes-associated erythema multiforme.

She was treated with oral acyclovir at the dose of 1000 mg/day in four daily doses for two weeks, along with acetaminophen, which induced rapid healing of the lesion (Fig. 1 A1, B1, C1 & D1).

Since these episodes promptly recur after discontinuation of therapy, the patient was advised to visit the clinic for regular maintenance visits for one year. Her three months followed up history did not reveal any recurrences.

Discussion

The incidence of EM was estimated as 0.3–7.4 cases per million persons, of which 20–30% are recurring [7, 8]. Mucosal lesions usually occur concurrently with skin lesions, although they can precede or follow the skin lesions. Oral manifestations of 70% of EM cases are characteristic [9]. Oral lesions show a predilection for lips, buccal mucosa, tongue and labial mucosa. They begin as oedematous and erythematous macular lesions of the lips and buccal mucosa. Lip swelling with blood-tinged crusted lesions is the hallmark of erythema multiforme. Vesiculobullous lesions, which progress to superficial erosions covered by pseudomembrane, are seen in advanced cases [10].

Nearly half of the recurrent EM cases were associated with an identifiable cause, such as infections, mostly herpes simplex virus or drug-induced hypersensitivity reaction. 7, 8 HSV DNA has been identified in 50% of patients with recurrent idiopathic erythema multiforme [11]. HSV infection is the predominant inciting event in cases of recurrent EM. Herpes-associated erythema multiforme (HAEM) characteristically manifests 7–10 days following an episode of HSV. 12 Though HSV infection may sometimes be clinically silent, HSV DNA can be detected in patients diagnosed with recurrent HAEM [1].

HSV infection of epithelial cells drives T helper 1- mediated inflammatory responses, which leads to the generation of circulating Langerhans cells precursors containing viral DNA particles, facilitating the transport of HSV-DNA fragments to distant skin sites. Further excessive recruitment of monocytes and activated T cells initiates the production of interferon-γ (IFN-γ) and leads to immune-mediated epidermal damage [13, 14].

Histopathology of Erythematous papular lesions exhibits mainly edema in the papillary layer with minimal or absent epidermal involvement. In contrast, classical target lesions reveal massive epidermal necrosis with resultant dermal interface bullae formation. [7].

Many treatment modalities have been utilized, such as anti-HSV drugs and anti-M. pneumoniae anti-biotics (macrolides, quinolones) and immunosuppressants, including corticosteroids [15]. In case of one virostatic drug resistance, the switch to an alternative drug, and if patients are non-responsive to virostatic drugs, dapsone therapy and newer treatment modalities, e.g., JAK-inhibitors or apremilast, might also be opted [7]. IFN-α treatment has been considered effective in reducing the intensity and duration of the disease in case of recurrence of HSV-associated EM [16]. However, patients with refractory disease may develop frequent recurrent episodes of EM after discontinuing the medications. Therefore, recurrent EM remains a complex problem for dermatologists to treat.

In conclusion, the presence of prodromal symptoms, recurrence and typical target-iris skin lesions in the present case pointed out to clinical diagnosis of recurrent HAEM, which was confirmed by serological tests. The oral manifestation of the present recurrent HAEM case exhibited plaque-like lesions with progressive necrosis. It is an unusual oral presentation of erythema multiforme and has not been reported yet to the best of our knowledge. Thus, the present case emphasizes that erythema multiforme should also be considered for the differential diagnosis of intra-oral plaque-like lesions.

Abbreviations

EM

Erythema Multiforme

HSV

Herpes Simplex Virus

ESR

Erythrocyte Sedimentation Rate

HAEM

Herpes-associated erythema multiforme

HSV DNA

Herpes Simplex Virus Double-Stranded DNA

IFN-i γ/α

Interferon-γ/α

M. pneumonia

Mycoplasma Pneumonia

JAK-inhibitors

Janus kinase inhibitors

Author’s contribution

KM, JT, TB, and SG prepared the manuscript, SD, SG and JT did the literature review, MP and SD critically reviewed the manuscript. All authors have reviewed and approved the final draft and are responsible for the content and similarity index of the manuscript.

Funding

This research did not receive any specific grant from the funding agencies in the public, commercial, or not for profit sectors.

Declarations

Conflict of interest

The authors have no conflict of interest to declare.

Ethical Approval

Not applicable since there is no ethical issue.

Informed Consent

was obtained from the above-described patient regarding the use of any clinical, radiographical, and other diagnostic and histopathological data or photographs for academic or publication purposes.